Disease, and Other Clinical Natural Kinds Barry Smith Gradualist Approaches to Health and Disease Berlin, March 23,

Natural Kind 2/ Synonyms: universal, type = entities of the sorts which are referred to by general terms of natural science Instances, particulars, individuals = entities of the sorts which can be observed in experiments of natural science

Old biology data 3/

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how to link the kinds of phenomena represented here 6/

or here 7

8

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10 or this?

answer: through annotation of data with terms from a controlled vocabulary or ‘ontology’ 11 sphingolipid transporter activity Holliday junction helicase complex

MouseEcotope GlyProt DiabetInGene GluChem sphingolipid transporter activity annotation using common ontologies allows navigation between databases 12

this allows integration of databases MouseEcotope GlyProt DiabetInGene GluChem Holliday junction helicase complex 13

facilitates retrieval of data brain 20 hindbrain 15 rhombomere 10 Query ‘brain’ without ontology 20 Query ‘brain’ with ontology 45 14

and supports logical reasoning over data 15

‘Ontology’ in PubMed 16/24

GO, in particular, is tremendously successful 17

$100 million invested in literature and data curation using GO over 11 million annotations relating gene products described in the UniProt, Ensembl and other databases to GO terms experimental results reported in 52,000 scientific journal articles manually annoted by expert biologists using GO 18

1.rooted in basic experimental biology 2.links people to data and to literature 3.links data to data across species (human, mouse, yeast, fly...) across granularities (molecule, cell, organ, organism, population) 4.links medicine to biological science 5.promotes cumulation of scientific knowledge in algorithmically tractable form 19 Benefits of the GO

A strategy for translational medicine Sjöblöm T, et al. analyzed 13,023 genes in 11 breast and 11 colorectal cancers using functional information captured by GO identified 189 genes as being mutated at significant frequency and thus as providing targets for diagnostic and therapeutic intervention. Science Oct 13;314(5797):

21 Google hits Jan ontology + Heidegger 58K ontology + Aristotle 77K ontology + philosophy327K ontology + software 468K ontology + database 594K ontology + information systems 702K

22 Comparison 2004/2012 ontology + Heidegger 58K 1.91M ontology + Aristotle 77K 1.66M ontology + philosophy 327K 4.91M ontology + software 468K 7.80M ontology + database 594K 10.20M ontology +information systems 702K 5.14M

Examples of Ontologies Foundational Model of Anatomy Ontology (FMA) Protein Ontology (PRO) Ontology for General Medical Science (OGMS) Plant Ontology (PO) Infectious Disease Ontology (IDO) Staph. aureus Ontology (IDO Sa) Malaria Ontology (IDO MAL) Influenza Ontology (IDO Flu) HIV Ontology (IDO HIV) 23

National Center for Biomedical Ontology (NIH Roadmap Center) 24 −Stanford Biomedical Informatics Research −The Mayo Clinic −University at Buffalo Department of Philosophy

25

26

GO supports only three types of annotation 27 what cellular component? what molecular function? what biological process? no diseases in GO

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29 RELATION TO TIME GRANULARITY CONTINUANTOCCURRENT INDEPENDENTDEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy) Anatomical Entity (FMA, CARO) Organ Function (FMP, CPRO) Phenotypic Quality (PaTO) Biological Process (GO) CELL AND CELLULAR COMPONENT Cell (CL) Cellular Component (FMA, GO) Cellular Function (GO) MOLECULE Molecule (ChEBI, SO, RnaO, PrO) Molecular Function (GO) Molecular Process (GO) OBO Foundry (first version, 2006) Yellow = Gene Ontology

30

Current OBO Foundry Ontologies Biological process (GO) Cellular component (GO) Chemical entities of biological interest Molecular function (GO) Phenotypic quality PRotein Ontology (PRO) Xenopus Anatomy and Development Zebrafish Anatomy and Development 31

Foundry ontologies under review Cell Ontology (CL) Foundational Model of Anatomy (FMA) Infectious Disease Ontology (IDO) Staph. aureus Ontology (IDO Sa) Malaria Ontology (IDO MAL) Influenza Ontology (IDO Flu) HIV Ontology (IDO HIV) Ontology for Biomedical Investigations (OBI) Ontology for General Medical Sciences (OGMS) Plant Ontology (PO) 32

Ontologies under construction Allergy Ontology Environment Ontology (EnvO) Immunology Ontology (IDO) Mental Functioning Ontology (MFO) Emotion Ontology (MFO-EM) Pain Ontology Mental Disease Ontology (MDO) Neurological Disease Ontology (ND) Vaccine Ontology (VO) 33

34 FMA has types and 3 million relations representing canonical adult human anatomy = the anatomy generated by the coordinated expression of the organism’s own structural genes. Canonical ≠ statistically normal 32 teeth two arms two legs one nose two nostrils two kidneys, … Foundational Model of Anatomy Ontology

Foundational Model of Anatomy (FMA) Pleural Cavity Pleural Cavity Interlobar recess Interlobar recess Mesothelium of Pleura Mesothelium of Pleura Pleura(Wall of Sac) Pleura(Wall of Sac) Visceral Pleura Visceral Pleura Pleural Sac Parietal Pleura Parietal Pleura Anatomical Space Organ Cavity Organ Cavity Serous Sac Cavity Serous Sac Cavity Anatomical Structure Anatomical Structure Organ Serous Sac Mediastinal Pleura Mediastinal Pleura Tissue Organ Part Organ Subdivision Organ Subdivision Organ Component Organ Component Organ Cavity Subdivision Organ Cavity Subdivision Serous Sac Cavity Subdivision Serous Sac Cavity Subdivision part_of is_a 35

An ontology is a controlled structured vocabulary that includes a backbone taxonomy (nodes connected by the is_a [subtype] relation) together with further logically defined relations such as part_of, regulated_by 36

ICD is not an Ontology ICD is not a classification of diseases It is a classification of people according to (roughly) those reasons for visiting a doctor that are significant for public health statistics US medical billing Practically useless for biomedical research 37

Basic Formal Ontology (BFO) A simple top-level ontology to support information integration in scientific research Serves as starting point for OBO Foundry ontologies Domain ontologies built by downward population 38

Basic Formal Ontology Continuant Occurrent Independent Continuant Dependent Continuant Organism Life Temperature 39

Example: The Cell Ontology

CONTINUANTOCCURRENT INDEPENDENTDEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy) Anatomical Entity (FMA, CARO) Organ Function (FMP, CPRO) Phenotypic Quality (PaTO) Organism-Level Process (GO) CELL AND CELLULAR COMPONENT Cell (CL) Cellular Component (FMA, GO) Cellular Function (GO) Cellular Process (GO) MOLECULE Molecule (ChEBI, SO, RNAO, PRO) Molecular Function (GO) Molecular Process (GO) rationale of OBO Foundry coverage (homesteading principle) GRANULARITY RELATION TO TIME 41

BFO and the 3 Gene Ontologies (GO) Continuant Occurrent Independent Continuant Dependent Continuant cell component biological process molecular function 42

Examples of users of BFO outside the OBO Foundry Interdisciplinary Prostate Ontology (IPO) Nanoparticle Ontology (NPO): Ontology for Cancer Nanotechnology Research Neural Electromagnetic Ontologies (NEMO) ChemAxiom – Ontology for Chemistry Ontology for Risks Against Patient Safety (RAPS/REMINE) (EU FP7) Petrochemical Ontology 43

Continuant Independent Continuant Dependent Continuant Non-realizable Dependent Continuant (quality) Realizable Dependent Continuant (function, role, disposition) TYPES INSTANCES

depends_on Continuant Independent Continuant thing Dependent Continuant quality example: temperature depends on bearer TYPES INSTANCES

Dependent Continuant Quality Realizable Dependent Continuant 46 DispositionFunctionRole of banana, to ripen of heart, to pump blood of employee, to work for pay

process of realization depends_on realizable Continuant Occurrent Independent Continuant bearer Realizable Dependent Continuant disposition Process of realization

Role (Externally-Grounded Realizable Entity) role =def. a realizable entity which exists because the bearer is in some special physical, social, or institutional set of circumstances in which the bearer does not have to be, and is not such that, if it ceases to exist, then the physical make-up of the bearer is thereby changed. 48

Disposition (Internally-Grounded Realizable Entity) disposition =def. a realizable entity which if it ceases to exist, then its bearer is physically changed, and whose realization occurs when this bearer is in some special physical circumstances, in virtue of the bearer’s physical make-up 49

Function (A Disposition Designed or Selected For) function =def. a disposition that exists in virtue of the bearer’s physical make-up,, and this physical make-up is something the bearer possesses because it came into being, either through evolution (in the case of natural biological entities) or through intentional design (in the case of artifacts), in order to realize processes of a certain kind. 50

Four distinct classificatory tasks 1.of people (patients, carriers, …) 2.of diseases (cases, instances, problems, …) 3.of courses of disease (symptoms, treatments…) 4.of representations (records, observations, data, diagnoses…) ICD confuses 1. & 2. Most standard terminologies confuse 2. and 4 51

Four distinct BFO categories 1.person (patient, carrier, …) – independent continuant 2.disease (case, instance, problem, …) – specifically dependent continuant 3.course of disease (symptom, treatment…) – occurrent 4.representation (record, datum, diagnosis…) – generically dependent continuant 52

Four distinct BFO categories 1.people (patients, carriers, …) – independent continuants 2.disease (case, instance, problem, condition …) – disposition 3.course of disease (symptom, episode, outbreak …) – realization of dispositions 4.representations (records, data, diagnoses…) – generically dependent continuants 53

Disposition Internally-Grounded Realizable Entity A disposition is a realizable entity which is such that, if it ceases to exist, then its bearer is physically changed, whose realization occurs, in virtue of the bearer’s physical make-up, when this bearer is in some special physical circumstances 54

Big Picture (Ontology for General Medical Science) 55

Elucidation of Primitive Terms ‘extended organism’ = the organism and all the material entities located within it ‘bodily feature’ = either a physical part of the extended organism, a bodily quality, or a bodily process. 56

Elucidation of Primitive Terms clinically abnormal - some bodily feature that (1) is not part of the life plan for an organism of the relevant type (unlike loss of milk teeth, aging or pregnancy), (2) is causally linked to an elevated risk either of pain or other feelings of illness, or of death or dysfunction, and (3) is such that the elevated risk exceeds a certain threshold level.* *Compare: baldness 57

Disorder A material entity (fiat object part) which is clinically abnormal and part of an extended organism Compare: Downtown Santa Barbara Mount Everest Peter Hucklenbroich’s pate 58

“Do Mountains Exist?”, Environment and Planning B, 30,

Definitions - Foundational Terms Pathological Process =def. – A bodily process that is clinically abnormal. Disease =def. – A disposition (i) to undergo pathological processes that (ii) exists in an organism because of one or more disorders in that organism. 60

61

Big Picture (Ontology for General Medical Science) 62

63

Definitions - Clinical Evaluation Terms Sign =def. – A bodily feature of a patient that is observed in a physical examination and is deemed by the clinician to be of clinical significance. (Objectively observable features) Symptom =def. – A experienced bodily feature of a patient that is observed by and observable only by the patient and is of the type that can be hypothesized by a patient to be a realization of a disease. (A restricted family of phenomena including pain, nausea, anger, drowsiness, which are of their nature experienced in the first person) Symptoms are subjective. But this does not mean that there is no objective fact of the matter whether a given symptom exists 64

Disease Course =Def. The sum of processes through which a given disease instance is realized. 65

independent continuant dependent continuant disposition disease organism John John’s disease occurrent process course of disease course of John’s disease TYPES INSTANCES

coronary heart disease John’s coronary heart disease 67 CHD in phase of asymptomatic (‘silent’) infarction CHD in phase of early lesions and small fibrous plaques stable angina CHD in phase of surface disruption of plaque unstable angina instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 in nature, no sharp boundaries here

human John 68 embryofetusadultneonateinfantchild instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 instantiates at t 6 in nature, no sharp boundaries here

portion of water this portion of H portion of ice portion of liquid water portion of gas instantiates at t 1 instantiates at t 2 instantiates at t 3 Phrase transitions TYPES INSTANCES

temperature John’s temperature 70 37ºC37.1ºC37.5ºC37.2ºC37.3ºC37.4ºC instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 instantiates at t 6 in nature, no sharp boundaries here

A disease is a disposition etiological process produces disorder bears disposition realized_in pathological process produces abnormal bodily features recognized_as signs & symptomsinterpretive process produces diagnosis used_in 71

Cirrhosis - environmental exposure Etiological process - phenobarbitol- induced hepatic cell death produces Disorder - necrotic liver bears Disposition (disease) - cirrhosis realized_in Pathological process - abnormal tissue repair with cell proliferation and fibrosis that exceed a certain threshold; hypoxia-induced cell death produces Abnormal bodily features recognized_as Symptoms - fatigue, anorexia Signs - jaundice, splenomegaly Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out cirrhosis suggests Laboratory tests produces Test results - elevated liver enzymes in serum used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease cirrhosis 72

Influenza - infectious Etiological process - infection of airway epithelial cells with influenza virus produces Disorder - viable cells with influenza virus bears Disposition (disease) - flu realized_in Pathological process - acute inflammation produces Abnormal bodily features recognized_as Symptoms - weakness, dizziness Signs - fever Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out influenza suggests Laboratory tests produces Test results - elevated serum antibody titers used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease flu 73

Huntington’s Disease - genetic Etiological process - inheritance of >39 CAG repeats in the HTT gene produces Disorder - chromosome 4 with abnormal mHTT bears Disposition (disease) - Huntington’s disease realized_in Pathological process - accumulation of mHTT protein fragments, abnormal transcription regulation, neuronal cell death in striatum produces Abnormal bodily features recognized_as Symptoms - anxiety, depression Signs - difficulties in speaking and swallowing Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out Huntington’s suggests Laboratory tests produces Test results - molecular detection of the HTT gene with >39CAG repeats used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease Huntington’s disease 74

Dispositions and Predispositions Some dispositions are predispositions to other dispositions. 75

HNPCC - genetic pre-disposition Etiological process - inheritance of a mutant mismatch repair gene produces Disorder - chromosome 3 with abnormal hMLH1 bears Disposition (disease) - Lynch syndrome realized_in Pathological process - abnormal repair of DNA mismatches produces Disorder - mutations in proto-oncogenes and tumor suppressor genes with microsatellite repeats (e.g. TGF-beta R2) bears Disposition (disease) - non-polyposis colon cancer realized in Symptoms (including pain) 76

Arterial Aneurysm Disposition – atherosclerosis realized in Pathological process – fatty material collects within the walls of arteries produces Disorder – artery with weakened wall bears Disposition – of artery to become distended realized_in Pathological process – process of distending produces Disorder – arterial aneurysm bears Disposition – of artery to rupture realized in Pathological process – (catastrophic event) of rupturing produces Disorder – ruptured artery, arterial system with dangerously low blood pressure bears Disposition – circulatory failure realized in Pathological process – exsanguination, failure of homeostasis produces Death 77

Definition: Etiology Etiological Process =def. – A process in an organism that leads to a subsequent disorder. Example: toxic chemical exposure resulting in a mutation in the genomic DNA of a cell; infection of a human with a pathogenic virus; inheritance of two defective copies of a metabolic gene The etiological process creates the physical basis of that disposition to pathological processes which is the disease. 78

Definitions - Diagnosis Clinical Picture =def. – A representation of a clinical phenotype that is inferred from the combination of laboratory, image and clinical findings about a given patient. Diagnosis =def. – A conclusion of an interpretive process that has as input a clinical picture of a given patient and as output an assertion to the effect that the patient has a disease of such and such a type. 79

Definitions - Qualities Manifestation of a Disease =def. – A bodily feature of a patient that is (a) a deviation from clinical normality that exists in virtue of the realization of a disease and (b) is observable. Observability includes observable through elicitation of response or through the use of special instruments. Preclinical Manifestation of a Disease =def. – A manifestation of a disease that exists prior to its becoming detectable in a clinical history taking or physical examination. Clinical Manifestation of a Disease =def. – A manifestation of a disease that is detectable in a clinical history taking or physical examination. Phenotype =def. – A (combination of) bodily feature(s) of an organism determined by the interaction of its genetic make-up and environment. Clinical Phenotype =def. – A clinically abnormal phenotype. 80

Big Picture 81

Systemic arterial hypertension Etiological process – abnormal reabsorption of NaCl by the kidney produces Disorder – abnormally large scattered molecular aggregate of salt in the blood bears Disposition (disease) - hypertension realized_in Pathological process – exertion of abnormal pressure against arterial wall produces Abnormal bodily features recognized_as Symptoms - Signs – elevated blood pressure Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out hypertension suggests Laboratory tests produces Test results - used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease hypertension 82

Type 2 Diabetes Mellitus Etiological process – produces Disorder – abnormal pancreatic beta cells and abnormal muscle/fat cells bears Disposition (disease) – diabetes mellitus realized_in Pathological processes – diminished insulin production, diminished muscle/fat uptake of glucose produces Abnormal bodily features recognized_as Symptoms – polydipsia, polyuria, polyphagia, blurred vision Signs – elevated blood glucose and hemoglobin A1c Symptoms & Signs used_in Interpretive process produces Hypothesis - rule out diabetes mellitus suggests Laboratory tests – fasting serum blood glucose, oral glucose challenge test, and/or blood hemoglobin A1c produces Test results - used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease type 2 diabetes mellitus 83

Type 1 hypersensitivity to penicillin Etiological process – sensitizing of mast cells and basophils during exposure to penicillin-class substance produces Disorder – mast cells and basophils with epitope-specific IgE bound to Fc epsilon receptor I bears Disposition (disease) – type I hypersensitivity realized_in Pathological process – type I hypersensitivity reaction produces Abnormal bodily features recognized_as Symptoms – pruritis, shortness of breath Signs – rash, urticaria, anaphylaxis Symptoms & Signs used_in Interpretive process produces Hypothesis - suggests Laboratory tests – produces Test results – occasionally, skin testing used_in Interpretive process produces Result - diagnosis that patient X has a disorder that bears the disease type 1 hypersensitivity to penicillin 84

Early Onset Alzheimer’s Disease Disorder – mutations in APP, PSEN1 and PSEN2 bears Disposition – impaired APP processing realized in Pathological process – accumulation of intra- and extracellular protein in the brain produces Disorder – amyloid plaque and neurofibrillary tangles bears Disposition – of neurons to die realized in Pathological process – neuronal loss produces Disorder – cognitive brain regions damaged and reduced in size bears Disposition (disease) – Alzheimer’s dementia realized in Symptoms – episodic memory loss and other cognitive domain impairment 85

Arterial Aneurysm Disposition – atherosclerosis – realized in Pathological process – fatty material collects within the walls of arteries – produces Disorder – artery with weakened wall – bears Disposition – of artery to become distended – realized_in Pathological process – process of distending – produces Disorder – arterial aneurysm – bears Disposition – of artery to rupture – realized in Pathological process – (catastrophic event) of rupturing – produces Disorder – ruptured artery, arterial system with dangerously low blood pressure – bears Disposition – circulatory failure – realized in Pathological process – exsanguination, failure of homeostasis – produces Death 86

Hemorrhagic stroke Disorder – cerebral arterial aneurysm – bears Disposition – of weakened artery to rupture – realized in Pathological process – rupturing of weakened blood vessel – produces Disorder – Intraparenchymal cerebral hemorrhage – bears Disposition (disease) – to increased intra-cranial pressure – realized in Pathological process – increasing intra-cranial pressure, compression of brain structures – produces Disorder – Cerebral ischemia, Cerebral neuronal death – bears Disposition (disease) – stroke – realized in Symptoms – weakness/paralysis, loss of sensation, etc 87

88 Only something like the disposition theory enables us to explain why a fracture is not a disease PETER HUCKLENBROICH −Radius fracture loco classico “ is a disease” Advantages of the Disposition Theory

89 PETER HUCKLENBROICH A disease entity is a set of possible alternative courses x has disease entity D ≡ (x has course D 1 ) or (x has course D 2 ) or … or (x has course D n ) Only something like the disposition theory can allow us to determine what does and what does not belong to this list.

90 Think of all the different temporal extents of the disease courses association with any given disease for those who die in an accident 5 seconds after catching the disease for those who have no treatment for those who have truly excellent treatment …

91 Think of all the different combination cases: of diseases with other diseases of diseases with complications of diseases at different stages of life of diseases with different environments in igloos in Ost-Thüringen in sub-Saharan Africa in space-ships …

92 Think of all the different types of patient: smoker non-smoker banana-leaf-smoker Am-Sonntag-bei-Mutti-Esser Aspirin-vor-dem-Schlafen-Gehen-Nehmer Auf-dem-Schiessplatz-Ohrstöpsel-Träger Auf-Weihnachtsmarkt-Lebkuchenherz-Käufer Auto-in-Waschstrasse-Abschliesser

93

human John 94 embryofetusadultneonateinfantchild instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 instantiates at t 6 in nature, no sharp boundaries here

portion of water this portion of H portion of ice portion of liquid water portion of gas instantiates at t 1 instantiates at t 2 instantiates at t 3 Phrase transitions

temperature John’s temperature 96 37ºC37.1ºC37.5ºC37.2ºC37.3ºC37.4ºC instantiates at t 1 instantiates at t 2 instantiates at t 3 instantiates at t 4 instantiates at t 5 instantiates at t 6 in nature, no sharp boundaries here